The Carbonic Anhydrase IX inhibitor SLC-0111 as emerging agent against the mesenchymal stem cell-derived pro-survival effects on melanoma cells

J Enzyme Inhib Med Chem. 2020 Dec;35(1):1185-1193. doi: 10.1080/14756366.2020.1764549.

Abstract

Mesenchymal stem cells (MSC) take part to solid tumour-associated stroma and critically influence progression of malignancy. Our study represents a striking example of melanoma progression to a more malignant and resistant phenotype promoted by MSC and the possibility to contrast this diabolic liaison using CAIX inhibitors. In particular, we demonstrated that melanoma cells exposed to a MSC-conditioned medium switch to a more malignant phenotype, characterised by resistance to programmed cell death and endowed with an epithelial-to-mesenchymal transition and stem cell characteristics. These effects were reversed abrogating MSC CAIX activity using SLC-0111, a CAIX inhibitor. Moreover, the acquisition by melanoma cells of a Vemurafenib-resistant phenotype upon MSC-conditioned medium exposure was removed when MSC were treated with SLC-0111. Therefore, MSC may profoundly reprogramme melanoma cells towards a wide resistant phenotype through CAIX involvement, as the use of SLC-0111 is able to contrast the development of this highly risky adaptation for disease progression.

Keywords: CAIX inhibitor; MSC; SLC-0111; melanoma.

MeSH terms

  • Carbonic Anhydrase IX / antagonists & inhibitors*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects*
  • Culture Media, Conditioned
  • Humans
  • Melanoma / pathology*
  • Mesenchymal Stem Cells / cytology*
  • Phenylurea Compounds / pharmacology*
  • Skin Neoplasms / pathology*
  • Sulfonamides / pharmacology*

Substances

  • Carbonic Anhydrase Inhibitors
  • Culture Media, Conditioned
  • Phenylurea Compounds
  • SLC-0111
  • Sulfonamides
  • Carbonic Anhydrase IX

Grant support

This study was financially supported by Istituto Toscano Tumori (ITT) (Decreto Dirigenziale Regione Toscana n. 5254 of 04/12/2013 to LC), Ente Cassa di Risparmio di Firenze (to LC) and Università degli Studi di Firenze. Elena Andreucci was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC fellowship for Italy) (FunRefID: 10.13039/501 100005010).